rs9986447

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000287.4(PEX6):c.883-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,609,494 control chromosomes in the GnomAD database, including 148,312 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10783 hom., cov: 31)

Exomes 𝑓: 0.43 ( 137529 hom. )

Consequence

PEX6
NM_000287.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0002058

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.428

Variant links:

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 6-42975041-A-G is Benign according to our data. Variant chr6-42975041-A-G is described in ClinVar as [Benign]. Clinvar id is 92791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42975041-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4 linkuse as main transcript	c.883-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13 linkuse as main transcript	c.883-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000287.4	P1	Q13608-1
PEX6	ENST00000244546.4 linkuse as main transcript	c.883-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1			Q13608-2

Frequencies

GnomAD3 genomes

AF:

0.362

AC:

54812

AN:

151618

Hom.:

10782

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.583

Gnomad AMR

AF:

0.324

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.405

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.453

Gnomad OTH

AF:

0.383

GnomAD3 exomes

AF:

0.373

AC:

93610

AN:

251010

Hom.:

19174

AF XY:

0.387

AC XY:

52530

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.228

Gnomad AMR exome

AF:

0.252

Gnomad ASJ exome

AF:

0.414

Gnomad EAS exome

AF:

0.105

Gnomad SAS exome

AF:

0.424

Gnomad FIN exome

AF:

0.402

Gnomad NFE exome

AF:

0.449

Gnomad OTH exome

AF:

0.409

GnomAD4 exome

AF:

0.427

AC:

622873

AN:

1457760

Hom.:

137529

Cov.:

AF XY:

0.430

AC XY:

311688

AN XY:

725384

show subpopulations

Gnomad4 AFR exome

AF:

0.224

Gnomad4 AMR exome

AF:

0.264

Gnomad4 ASJ exome

AF:

0.413

Gnomad4 EAS exome

AF:

0.125

Gnomad4 SAS exome

AF:

0.432

Gnomad4 FIN exome

AF:

0.394

Gnomad4 NFE exome

AF:

0.453

Gnomad4 OTH exome

AF:

0.408

GnomAD4 genome

AF:

0.361

AC:

54841

AN:

151734

Hom.:

10783

Cov.:

AF XY:

0.358

AC XY:

26570

AN XY:

74154

show subpopulations

Gnomad4 AFR

AF:

0.230

Gnomad4 AMR

AF:

0.324

Gnomad4 ASJ

AF:

0.408

Gnomad4 EAS

AF:

0.105

Gnomad4 SAS

AF:

0.404

Gnomad4 FIN

AF:

0.405

Gnomad4 NFE

AF:

0.453

Gnomad4 OTH

AF:

0.381

Alfa

AF:

0.400

Hom.:

6878

Bravo

AF:

0.346

Asia WGS

AF:

0.250

AC:

870

AN:

3478

EpiCase

AF:

0.457

EpiControl

AF:

0.459

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2016	Variant summary: The PEX6 c.883-3T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 45827/121356 control chromosomes (9493 homozygotes) at a frequency of 0.3776245, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic PEX6 variant (0.0019365), indicating that this variant is a benign polymorphism. Multiple clinical labs have classified the variant as benign. Taken together, this variant is classified as benign. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2013	- -

Peroxisome biogenesis disorder 4A (Zellweger)

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B;C4225267:Heimler syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Heimler syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Zellweger spectrum disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Peroxisome biogenesis disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Peroxisome biogenesis disorder 4B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

Cadd

Benign

8.3

Dann

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.016

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over